Keywords: calcineurin inhibitor, children, nephrotic syndrome, rituximab, steroid

Background Efficacy of rituximab in the management of idiopathic nephrotic syndrome in children is well-established, however there is limited evidence of its efficacy in children with steroid- and calcineurin inhibitor-dependent nephrotic syndrome (CNI-SDNS).

Objective To investigate the efficacy and safety of rituximab in children with CNI-SDNS.

Methods We conducted a comprehensive search for relevant RCTs in PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Google Scholar. Eligible RCTs were included, assessed for risk of bias using the Revised Cochrane risk-of-bias tool for randomized trials, and summarized narratively.

Results A total of five RCTs (299 children) were included in the review. Rituximab was effective in maintaining remission and preventing relapse in pediatric CNI-SDNS patients, in a manner potentially superior to conventional therapy. Furthermore, rituximab successfully resulted in a higher rate of steroid and CNI withdrawal, along with prolonged drug-free period. However, the benefits of rituximab in children with focal segmental glomerulosclerosis (FSGS) remains equivocal. The drug was generally well-tolerated, both in the short-term and long-term, with a low incidence of adverse events and infusion reactions, typically of mild and reversible nature.

Conclusion Rituximab appears to be effective and safe in treating children with CNI-SDNS, offering potential benefits in reducing dependence on steroids and CNIs. Larger trials comparing the effectiveness of rituximab specifically between children with minimal change disease (MCD) and FSGS are warranted to further validate and strengthen our findings.

1. Vivarelli M, Gibson K, Sinha A, Boyer O. Childhood nephrotic syndrome. The Lancet 2023;402:809–24. DOI: https://doi.org/10.1016/S0140-6736(23)01051-6
2. Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. The Lancet 2018;392:61–74. DOI: https://doi.org/10.1016/S0140-6736(18)30536-1
3. Ehren R, Benz MR, Brinkkötter PT, Dötsch J, Eberl WR, Gellermann J, et al. Pediatric idiopathic steroid-sensitive nephrotic syndrome: diagnosis and therapy - short version of the updated German best practice guideline (S2e) — AWMF register no. 166-001, 6/2020. Pediatr Nephrol 2021;36:2971–85. DOI: https://doi.org/10.1007/s00467-021-05135-3
4. Ravani P, Lugani F, Drovandi S, Caridi G, Angeletti A, Ghiggeri GM. Rituximab vs low-dose mycophenolate mofetil in recurrence of steroid-dependent nephrotic syndrome in children and young adults: A randomized clinical trial. JAMA Pediatr 2021;175:631–2. DOI: https://doi.org/10.1001/jamapediatrics.2020.6150
5 Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane handbook for systematic reviews of interventions version 6.0 (updated July 2019). Cochrane; 2019. DOI: https://doi.org/10.1002/9781119536604
6. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372. DOI: https://doi.org/10.1136/BMJ.N71
7. Sterne JAC, Savovi? J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:I4898. DOI: https://doi.org/10.1136/bmj.l4898
8. McKenzie J, Brennan S. Chapter 12: Synthesizing and presenting findings using other methods. Cochrane, 2024 [updated 2019 Oct 31; cited 2024 Feb 10]. In: Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al., editors. Cochrane Handb. Syst. Rev. Interv. version 6.5. Available from: https://training.cochrane.org/handbook/
9. Ravani P, Colucci M, Bruschi M, Vivarelli M, Cioni M, DiDonato A, et al. Human or chimeric monoclonal anti-CD20 antibodies for children with nephrotic syndrome: A superiority randomized trial. J Am Soc Nephrol JASN 2021;32:2652–63. DOI: https://doi.org/10.1681/ASN.2021040561
10. Ahn YH, Kim SH, Han KH, Choi HJ, Cho H, Lee JW, et al. Efficacy and safety of rituximab in childhood-onset, difficult-to-treat nephrotic syndrome: A multicenter open-label trial in Korea. Medicine (Baltimore) 2018;97:e13157. DOI: https://doi.org/10.1097/MD.0000000000013157
11. Boumediene A, Vachin P, Sendeyo K, Oniszczuk J, Zhang S-Y, Henique C, et al. NEPHRUTIX: A randomized, double-blind, placebo vs Rituximab-controlled trial assessing T-cell subset changes in minimal change nephrotic syndrome. J Autoimmun 2018;88:91–102. DOI: https://doi.org/10.1016/j.jaut.2017.10.006
12. Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, et al. Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol JASN 2012;23:1117–24. DOI: https://doi.org/10.1681/ASN.2011080775
13. Ravani P, Magnasco A, Edefonti A, Murer L, Rossi R, Ghio L, et al. Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial. Clin J Am Soc Nephrol CJASN 2011;6:1308–15. DOI: https://doi.org/10.2215/CJN.09421010
14. Hanif N, Anwer F. Rituximab. StatPearls [Internet]. 2023 Sep 26 [cited 2024 Feb 1]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564374/
15. Chan EY-H, Yap DY-H, Colucci M, Ma AL-T, Parekh RS, Tullus K. Use of rituximab in childhood idiopathic nephrotic syndrome. Clin J Am Soc Nephrol CJASN 2023;18:533–48. DOI: https://doi.org/10.2215/CJN.08570722
16. Hansrivijit P, Cheungpasitporn W, Thongprayoon C, Ghahramani N. Rituximab therapy for focal segmental glomerulosclerosis and minimal change disease in adults: A systematic review and meta-analysis. BMC Nephrol 2020;21. DOI: https://doi.org/10.1186/s12882-020-01797-7
17. Gauckler P, Shin JI, Alberici F, Audard V, Bruchfeld A, Busch M, et al. Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown? Autoimmun Rev 2020;19:102671. DOI: https://doi.org/10.1016/j.autrev.2020.102671
18. Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int 2021;100:S1–276. DOI: https://doi.org/10.1016/j.kint.2021.05.021
19. Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients’ management. Nat Rev Nephrol 2013;9:154–69. DOI: https://doi.org/10.1038/nrneph.2012.289
20. Chaki A, Rahman F, Arju J, Al Mamun A-, Jesmin T, Huque SS, et al. Rituximab in steroid resistant nephrotic syndrome. Paediatr Indones 2019;59:175–82. DOI: https://doi.org/10.14238/pi59.4.2019.175-82
21. Kallash M, Smoyer WE, Mahan JD. Rituximab use in the management of childhood nephrotic syndrome. Front Pediatr 2019;7:178. DOI: https://doi.org/10.3389/fped.2019.00178
22. Maxted AP, Dalrymple RA, Chisholm D, McColl J, Tse Y, Christian MT, et al. Low-dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome. Pediatr Nephrol 2019;34:855–63. DOI: https://doi.org/10.1007/s00467-018-4172-3
23. Qader MA, Vivarelli M. Children with steroid dependent nephrotic syndrome: Rituximab or tacrolimus? It’s all in the timing. Kidney Int Rep 2023;8:1708–10. DOI: https://doi.org/10.1016/j.ekir.2023.07.016
24. Basu B, Preussler S, Sander A, Mahapatra TKS, Schaefer F. Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome. BMC Nephrol 2020;21:520. DOI: https://doi.org/10.1186/s12882-020-02153-5
25. Specialised Commissioning Team, NHS England. Clinical commissioning policy: Rituximab for the treatment of relapsing steroid sensitive nephrotic syndrome. United Kingdom: NHS England; 2015 [cited 2024 Feb 15]. Available from: https://www.england.nhs.uk/wp-content/uploads/2018/07/Rituximab-for-the-treatment-of-relapsing-steroid-sensitive-nephrotic-syndrome.pdf
26. Takura T, Takei T, Nitta K. Cost-effectiveness of administering rituximab for steroid-dependent nephrotic syndrome and frequently relapsing nephrotic syndrome: A preliminary study in Japan. Sci Rep 2017;7:46036. DOI: https://doi.org/10.1038/srep46036
27. Tan L, Li S, Yang H, Zou Q, Wan J, Li Q. Efficacy and acceptability of immunosuppressive agents for pediatric frequently-relapsing and steroid-dependent nephrotic syndrome: A network meta-analysis of randomized controlled trials. Medicine (Baltimore) 2019;98:e15927. DOI: https://doi.org/10.1097/MD.0000000000015927